Processes for coating a carrier with microparticles

ABSTRACT

Processes for coating a carrier with microparticles of a drug are described. For example, a coated carrier can be obtained in a one-stage process that entails evaporating a solvent from microdroplets of a solution containing an API to obtain dry microparticles, which are then coated on the carrier.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/693,602, filed Jan. 26, 2010, which claims priority to U.S.Provisional Patent Application No. 61/147,287, filed Jan. 26, 2009, thedisclosures of which are incorporated herein by reference in theirentireties and for all purposes.

FIELD OF THE INVENTION

The present invention relates to processes for coating carriers withmicroparticles.

BACKGROUND OF THE INVENTION

Several processes for coating carriers with particles are known in theart. One typical process is performed by using a fluidized bed as thecarrier. A fluidized bed is formed when a quantity of a solidparticulate substance (usually present in a holding vessel) is placedunder appropriate conditions to cause the solid/fluid mixture to behaveas a fluid. This is usually achieved by the introduction of pressurizedfluid through the particulate medium. This results in the medium thenhaving many properties and characteristics of normal fluids.

According to one process known in the art, droplets of a suspension aresprayed on a fluidized bed, normally using a Wurster apparatus. TheWurster apparatus generally includes a container with a cylindricalpartition extending upwardly therein, and with a perforated plate orscreen at the lower end thereof to define a bottom wall for theparticles. The partition is spaced above the perforated plate. The areawithin the cylindrical partition defines the upbed of the container,while the area outside the partition defines the downbed of thecontainer. The perforated plate includes an area of large perforationsand a greater percentage of perforated open area through which air flowsinto the upbed at an increased velocity, and an area of perforationswith a lower percentage of open area through which air flows into thedownbed at a decreased velocity. The higher velocity air in the upbedarea transports the particles for coating, layering, and drying of acoating solution sprayed from a spray nozzle extending upwardly throughthe perforated plate and into the upbed area. The particles thenencounter the lower velocity air in the expansion chamber above thepartition. When the air velocity is insufficient to support the product,the particles fall into the downbed area for reentry into the highervelocity air, such that a cycle of coating in the upbed area and dryingin the downbed area is achieved. Various forms of the Wurster apparatusand process are disclosed in U.S. Pat. Nos. 2,648,609, 2,799,241,3,089,824, 3,196,827, 3,207,824, and 3,253,944.

In the pharmaceutical industry, an API (active pharmaceuticalingredient) is commonly introduced into the patient's body deposed on acarrier. Carriers are substances which are used to improve theperformance of the dose form by increasing the uniformity of the blendand keep the API particles from aggregating. Many substances are knownto be suitable as carriers in the pharmaceutical industry, for example:micro-crystalline cellulose, lactose and mannitol. Those skilled in theart generally choose a carrier based on its particle size distributionand solubility properties.

The Wurster apparatus method of coating results in carriers which arecoated with a layer of API crystals with a large range of sizes. Thislayer is created due to the adherence of the droplets to the carrierparticles prior to the evaporation of the solvent. In this method, theparticles of API are suspended in a dispersion liquid. If the APIparticles are very small, they may aggregate and the suspension will notbe uniform. In many cases, the API particles are not stable in thesuspension, and the process should be performed soon after the creationof the suspension.

Furthermore, it may be readily understood that the Wurster apparatusmethod is not suitable for coating carrier particles with microdropletsof API solution or air-suspended dry microparticles because of the lowprobability of a microparticle or microdroplet to collide with a carrierparticle. In this case, the microparticles might escape through thefiltering system and the material will be lost.

Many efforts have been made to formulate suitable therapeutic agents asdry powders for delivery via inhalers. Typically, the formulations areproduced by drying the active agent in the presence of certainexcipients, such as polysaccharides or citrate, to enhance stabilityduring the drying process or in storage.

CA-A-2136704 discloses a product obtained by spray-drying a medicinalsubstance such as insulin (among many others) and a carrier.WO-A-9735562 discloses spray-drying a solution of insulin and apolysaccharide. WO-A-9524183 is directed primarily to a dry powder thatcomprises insulin and a carrier material, typically a saccharide, in theform of an amorphous powder of microparticles obtained by spray-drying.WO95/23613 discloses a spray-dried DNase formulation. U.S. Pat. No.6,926,908 discloses spray-dried therapeutic agent at highconcentrations.

There is a need in the art for methods of coating carriers withmicroparticles of an API that are either suspended in air or formed frommicrodroplets.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is an SEM image of cellulose coated with nano-atomized API.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a process comprisingthe steps of:

-   -   a. providing microdroplets of a solution of an API and a        solvent;    -   b. evaporating the solvent from the microdroplets to obtain dry        microparticles, and    -   c. contacting the microparticles with a static carrier bed or        periodically agitated carrier bed to obtain a carrier coated        with microparticles.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses processes for coating a static orperiodically agitated carrier bed with microparticles.

In preferred embodiments the invention provides carriers coated withmicroparticles, wherein the microparticles can dissociate from thecarrier.

The carriers which are obtained by the above process are coated bymicroparticles which are preferably generally round in shape andpreferably have a relatively narrow range of sizes. Use of roundmicroparticles is important, for example, in the inhalationpharmaceutical products industry since the relatively small, roundparticles flow more easily through the respiratory system and thereforethe availability of the API is improved.

The round shape of the microparticle also provides minimal contact ofthe microparticle with the carrier, thus improving the ability of theAPI to separate from the carrier on which it is deposed and affectingthe target site to a better extent.

Any API can be used in the practice of the present invention. Examplesinclude docetaxel, other cytotoxic drugs, risperidone, beclomethasone,fluticasone, budesonide, other steroid drugs, salbutamol, terbutaline,ipratropium, oxitropium, formoterol, salmeterol, valsartan, ezetimibe,paliperidone, aprepitant, tacrolimus, sirolimus, everolimus andtiotropium.

As used herein “static carrier bed” is a layer of carrier particles suchas lactose or micro-crystalline cellulose which is statically laid on asupporting mesh.

As used herein “periodically agitated carrier bed” is a static carrierbed that is periodically agitated by a suitable agitator to homogenizethe powder and expose new carrier particles to the coating process.

As used herein “SEM” is Scanning-Electron Microscope, used to observeparticles and structures in the micro-range. This microscope images thesample surface by scanning it with a high-energy beam of electrons in araster scan pattern.

In a specific embodiment, the process of the present invention comprisesthe steps of:

-   -   a. providing microdroplets of a solution of at least one API and        a solvent;    -   b. evaporating the solvent from the microdroplets to obtain        microparticles, and    -   c. contacting the microparticles with a static carrier bed or a        periodically agitated carrier bed to obtain a carrier coated        with microparticles.

Preferably, the microdroplets are obtained by an atomizer. An atomizeris an apparatus which creates a spray of small droplets from a liquid,solution or a suspension. Many types of atomizers are known, varying inthe generated droplet size and mechanism of operation. Jet-atomizerscreate droplets by co-spraying them with a jet of air. Rotary diskatomizers create droplets by creating a layer of liquid on a rotatingdisc. Ultrasonic atomizers disperse the liquid into droplets by means ofultrasonic vibrations. Nano-atomizers create droplets by creating anultra-thin layer of liquid on a membrane and spraying the atomizationgas through the membrane, breaking the thin liquid layers to sub-microndroplets. Atomizers differ in performance and in parameters such asdroplet size, droplet velocity, and droplet concentration in the carriergas.

Several atomizers are available for the purpose of preparing themicrodroplets, for example Ultra Sonic Atomizer (SonoteK,http://www.sonozap.com/Ultrasonic_Atomizer.html) and Nano-Solnano-atomizer (http://www.nanosol-il.com/prods.html) which is describedin U.S. Pat. No. 6,899,322. The atomizer makes use of a gas, typicallynitrogen or CO₂ gas, as the spraying and conveying gas (the gas thatgenerates the microdroplets and then carries them to the target) so thatthe microdroplets are released from the atomizer surrounded by gas.

The obtained microdroplets preferably have an average diameter of about1-15 micrometers, preferably 1-3 micrometers. Preferably, the solutionfrom which the microdroplets are obtained is a solution of an API whichis completely dissolved in an appropriate solvent or surfactant. Theratio of API to solvent or surfactant preferably varies between about 1%to about 30% and one may adjust this ratio of API to solvent orsurfactant to obtain microdroplets and particles at different sizes ordifferent density. The solution may include other ingredients, such asadditional API, preservatives, stabilizers, colorants, etc.

A preferred surfactant is selected from the group consisting of polyvinyl alcohol (PVA), polysorbate 80 (polyoxyethylene (20) sorbitanmonooleate), polysorbate 20 (polyoxyethylene (20) sorbitan monolaurate),poloxamer 188, polyethoxylated 35 castor oil (cremophor EL),polyethoxylated 40 hydrogenated castor oil or a mixture thereof.

In order to direct the gas stream and microdroplets (or microparticles,if spontaneous evaporation has already taken place) flow, through apipe, towards a vessel which contains the static carrier, vacuum ispreferably applied to the down-stream side of the carrier bed. Thevacuum suction is preferably just high enough to overcome the pressuredrop over the bed and provide laminar air flow. Preferably, the pipe isdesigned to enable the stream of gas and microdroplets/particles to flowin a laminar flow manner, thereby reducing to a minimum the amount ofparticles which adhere to the walls of the pipes and vessels.

Evaporation of the microdroplets to obtain microparticles may beachieved spontaneously due to the relatively large surface face of eachmicrodroplet. It may also be achieved, for example, by heating the pipethrough which the stream of gas and microdroplets pass through, towardsthe vessel which contains the static bed. Optionally, the vessel inwhich the carrier bed is situated may also be heated to assistevaporation. Typically, temperatures of about 40-100° C. along part ofthe pipe length will be sufficient to evaporate the solvent of themicrodroplet.

Preferably, when reaching the vessel in which the static or periodicallyagitated carrier is situated, the solvent has already partiallyevaporated from the microdroplets to obtain moist microparticles; morepreferably the solvent has already completely evaporated from themicrodroplets to obtain dry microparticles. One skilled in the art woulddetermine the appropriate evaporation conditions so that he may controlthe water content in the microparticle. In some cases, moist particleswill allow better adhesion of the microparticles to the carrier.

Preferably the microparticles which are obtained are round in shape.This may be achieved at least in part by evaporating the solvent fromthe microdroplet prior to contact with the carrier. The drymicroparticles preferably have an average diameter of about 100 nm toabout 10,000 nm, preferably about 200-5,000, more preferably about500-5,000 nm, most preferably about 500-1,000 nm.

Preferably the static carrier is an excipient which is known to besuitable in the pharmaceutical industry. Examples for suitable carriersare: microcrystalline cellulose (e.g., Avicel 101), lactose, andmannitol. Typically, the carrier is chosen according to the API which isdeposited thereon and according to the route of administration. Theparticle size distribution of carrier particles may have an effect onefficiency of deposition and pressure drop across the bed. There areknown methods to control and manipulate the size of carrier particlessuch as screening and milling.

Typically, the carrier is situated in the vessel on a mesh to ensurethat the carrier particles do not escape from the vessel due to thevacuum. The mesh may be made of stainless steel, polyester, teflon, etc.One skilled in the art would choose the appropriate mesh having holes ata certain size according to the size of the carrier particles ofinterest, so that the mesh will enable the passage of the spraying andconveying gas without the escaping of carrier particles. For example,when using Avicel 101 it was found that the size of the holes ispreferably between about 50 to about 100 microns.

The static carrier bed is typically agitated every 15 minutes using astirrer to expose a new surface of the carrier to be coated by the drymicroparticles. This serves to improve efficiency and consistency of thedry microparticles deposition.

Typically, once the gas stream and microdroplets/particles reach thevessel, the conveying gas (e.g., nitrogen) is readily removed from thevessel due to the vacuum through the spaces that are within the carrierbed and mesh. The dry microparticles, however, undergo deposition on thecarrier since the carrier serves as a filter that prevents themicroparticles from escaping out of the vessel.

In a preferred embodiment, the process is carried out in one stage. Asused herein a “one stage process” refers to a process in which themicroparticles are dried while it is being carried by a conveying gas toand coated onto the carrier. A process in which microparticles are driedthen admixed with a carrier in a separate step, for example, would notbe encompassed by the term “one stage process.”

Having thus described the invention with reference to particularpreferred embodiments and illustrative examples, those in the art canappreciate modifications to the invention as described and illustratedthat do not depart from the spirit and scope of the invention asdisclosed in the specification. The Examples are set forth to aid inunderstanding the invention but are not intended to, and should not beconstrued to, limit its scope in any way. Absent statement to thecontrary, any combination of the specific embodiments described aboveare consistent with and encompassed by the present invention.

EXAMPLES

The nano atomizer which was used in the examples is manufactured byNanoSol, utilizing 4 spraying elements. The experiments were performedusing valsartan API. Polymorphs of valsartan have been described in WO04083192A1 and processes for its preparation have been disclosed in WO20040094391, both of which are incorporated herein by reference. Itshould be readily understood that the examples may apply for differentAPIs. The invention does not contain any inherent limitations on thechoice of solvent and solute.

Example 1 Spray Coating of Cellulose with Valsartan API

A solution of 2% Valsartan in a solvent (ethanol) was sprayed by a nanoatomizer to produce microdroplets having an average size of about 1-10micrometers. Nitrogen gas was used as the spraying and conveying gas.The carrier was Avicel 101, screened by a 75 μm screen to remove fineparticles. The purpose of the sieving was to decrease pressure drop overthe bed. The bed collecting device was a modified filter-drier (modelfilterlab 80 by GL filtration LTD). The modification included aconnection of a vacuum pump to the bottom of the vessel in order toremove the nitrogen and direct the flow of suspended particles andmicrodroplets to the bed. A second modification made to the instrumentwas removal of sintered metal filter media and replacing it with asupported mesh made of Polyester.

The piping connecting the atomizer and the collection vessel wasdesigned to maintain laminar flow of the suspended particles andmicrodroplets. Therefore, deposition of particles on the piping wallswas minimal. A heating element was installed in one segment of the pipeto assist evaporation of ethanol.

The pressure drop at the bed increased during the nano spray-coating. Inabout 20 minutes it rose from 30 mbar to 219 mbar. It was found that byagitating the bed, the pressure drop reverted back to its originalvalue. In this example, 6 cycles were performed with total spraying timeof 131 minutes.

Two samples were analyzed for valsartan content after different sprayingtimes: one after 46 minutes and the other after 131 minutes. The sampleswere also observed by SEM.

From the SEM photos (see FIG. 1) it can be observed that the roundedshaped API particles (˜100 nm-˜10000 nm) were deposed on the carrier.From the assay analysis the API weight percentage (based on the totalweight of API and carrier) was raised during the process: 4.21% after 46minutes of spraying and 9.95% after 131 minutes.

What is claimed is:
 1. A process comprising the steps of: (a) providinga conveying gas carrying microdroplets of a solution comprising anactive pharmaceutical ingredient and a solvent; (b) evaporating thesolvent from the microdroplets to obtain at least partially driedmicroparticles comprising the active pharmaceutical ingredient carriedby the conveying gas; and (c) contacting the at least partially driedmicroparticles comprising the active pharmaceutical ingredient carriedby the conveying gas with a carrier bed to obtain a carrier coated withmicroparticles, wherein the carrier bed is a static carrier bed or aperiodically agitated carrier bed.
 2. The process of claim 1, whereinthe active pharmaceutical ingredient is selected from the groupconsisting of: docetaxel, risperidone, beclomethasone, fluticasone,budesonide, salbutamol, terbutaline, ipratropium, oxitropium,formoterol, salmeterol, valsartan, ezetimibe, paliperidone, aprepitant,tacrolimus, sirolimus, everolimus and tiotropium.
 3. The process ofclaim 1, wherein the carrier is selected from the group consisting of:microcrystalline cellulose, lactose, and mannitol.
 4. The process ofclaim 1, wherein the microparticles have an average diameter of about100 nm to about 10,000 nm.
 5. The process of claim 4, wherein themicroparticles have an average diameter of about 200 nm to about 5,000nm.
 6. The process of claim 5, wherein the microparticles have anaverage diameter of about 500 nm to about 5,000 nm.
 7. The process ofclaim 6, wherein the microparticles have an average diameter of about500 nm to about 1,000 nm.
 8. The process of claim 1, wherein the solventis ethanol.
 9. A process comprising the steps of: (a) providing aconveying gas carrying microdroplets of a solution of an activepharmaceutical ingredient and a solvent; (b) evaporating the solventfrom the microdroplets to obtain at least partially dried microparticlesof the active pharmaceutical ingredient carried by the conveying gas;and (c) coating a carrier with the at least partially driedmicroparticles of the active pharmaceutical ingredient carried by theconveying gas.
 10. The process of claim 9, wherein the carrier isselected from the group consisting of: microcrystalline cellulose,lactose, and mannitol.
 11. The process of claim 9, wherein themicrodroplets have an average diameter of about 1 to about 15micrometers.
 12. The process of claim 9, wherein the microparticles havean average diameter of about 100 nm to about 10,000 nm.
 13. The processof claim 12, wherein the microparticles have an average diameter ofabout 200 nm to about 5,000 nm.
 14. The process of claim 13, wherein themicroparticles have an average diameter of about 500 nm to about 5,000nm.
 15. The process of claim 14, wherein the microparticles have anaverage diameter of about 500 nm to about 1,000 nm.
 16. The process ofclaim 9, wherein the coating step comprises contacting themicroparticles with a carrier bed to obtain a carrier coated withmicroparticles.
 17. The process of claim 9, wherein the activepharmaceutical ingredient is selected from the group consisting of:docetaxel, risperidone, beclomethasone, fluticasone, budesonide,salbutamol, terbutaline, ipratropium, oxitropium, formoterol,salmeterol, valsartan, ezetimibe, paliperidone, aprepitant, tacrolimus,sirolimus, everolimus and tiotropium.
 18. The process of claim 9,wherein the solvent is ethanol.
 19. The process of claim 1, wherein theevaporating step comprises completely evaporating the solvent from themicroparticles such that the microparticles are dry when coated on thecarrier.
 20. The process of claim 9, wherein the evaporating stepcomprises completely evaporating the solvent from the microparticlessuch that the microparticles are dry when coated on the carrier.
 21. Theprocess of claim 1, wherein the process is a one stage process.
 22. Theprocess of claim 9, wherein the process is a one stage process.
 23. Theprocess of claim 1 further comprising applying vacuum to the down-streamside of the carrier bed to provide laminar flow to the conveying gas.24. The process of claim 9 further comprising applying vacuum to thedown-stream side of the carrier bed to provide laminar flow to theconveying gas.